EP1370280A2 - Interleukine 2 stabilisee - Google Patents

Interleukine 2 stabilisee

Info

Publication number
EP1370280A2
EP1370280A2 EP01952296A EP01952296A EP1370280A2 EP 1370280 A2 EP1370280 A2 EP 1370280A2 EP 01952296 A EP01952296 A EP 01952296A EP 01952296 A EP01952296 A EP 01952296A EP 1370280 A2 EP1370280 A2 EP 1370280A2
Authority
EP
European Patent Office
Prior art keywords
histidine
formulation
preparation
formulations
sucrose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP01952296A
Other languages
German (de)
English (en)
Other versions
EP1370280B1 (fr
Inventor
Wei Wang
Rajiv Nayar
Michael A. Shearer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aicuris GmbH and Co KG
Original Assignee
Bayer AG
Bayer Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=24424265&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1370280(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Bayer AG, Bayer Corp filed Critical Bayer AG
Publication of EP1370280A2 publication Critical patent/EP1370280A2/fr
Application granted granted Critical
Publication of EP1370280B1 publication Critical patent/EP1370280B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention is generally related to the field of pharmaceutical formulations. More specifically, the invention is directed to a stabilized, therapeutically active Interleukin-2 formulation capable of selectively activating T cells (PHA-blasts) and, very preferably, including an IL-2 mutein demonstrating reduced activation of Natural Killer ("NK”) cells.
  • PHA-blasts T cells
  • NK Natural Killer
  • the stabilized compositions having the preferred properties include variants of IL-2 described below.
  • Interleukin 2 is a potent immune stimulator, activating diverse cells of the immune system, including T cells, B cells, and monocytes.
  • IL-2 is also a potent and critical growth factor of T cells. It was by virtue of these activities that IL-2 was tested for its ability to treat cancer.
  • Human IL-2 is a FDA approved drug for the treatment of metastatic renal carcinoma and metastatic melanoma. The use of IL-2 in eligible patients is restricted due to the severe toxicity associated with IL-2 therapy; it is estimated that at best only 20% of eligible patients actually receive therapy.
  • the toxicities associated with IL-2 therapy include severe fever, nausea, vomiting, vascular leak. and serious hypotension. Despite these toxicities, however, IL-2 is effective for its approved indications. Variants of IL-2 having reduced toxicity are the subject matter of application WO 99/60128.
  • compositions of recombinant interleuken-2 and formulation processes (US patent No. 5,037,644) describes formulations which are either in freeze-dried or liquid form.
  • the excipients of the formulation include a non- ionic polymeric detergent such as Triton X405, Triton X305, PEG (4000) monostearate, Tween 80 and Tween 20 at concentrations of about 0.001% to about 5%, a bulking/stabilizing agent such as sucrose, fructose, dextrose, maltose, glucose, dextran, mannitol, sorbitol, inositol, galactitol, xylitol, lactose, trehalose, human serum albumin and bovine serum albumin, and a buffering agent such as glycine, citrate, or phosphate in a concentration range from about 10 mM to about 50 mM with a pH ranging from about 3 to
  • Formulations may contain one or a combination of stabilizers such as arginine, carnitine, betaine, pyridoxme polyvinylpyrrolidone, salts of capric acid, sugars, sugar alcohols, serum albumin, and citrate at pH 5.0-8.5 buffer.
  • concentration of stabilizers is between 0.2 and 3.0% (w/v) for arginine, between 0.2 and 3.0% (w/v) for carnitine, between 2 and 6% (w/v) for sucrose, and 0.01 and 0.3M for citrate.
  • Stable composition of interleukin-2 and albumin (US patent No. 4,645,830) describes a stable aqueous formulation that contains human serum albumin (0.1 - 50 mg/ml) with or without a reducing excipient such as glutathione, thioctic acid, N-acetylcysteine, or ascorbic acid (concentration of 0.05 - 20 mg/ml) at pH between 3 to 5.5.
  • the albumin formulation may contain a monoamino aliphatic amino acid, a cyclic amino acid, a monosaccharide, a sugar alcohol or monoamino aliphatic amino acid (concentration of 5 to 50 mg/ml).
  • Figure 1 is a graph illustrating the optimum pH range for an aqueous IL-2 solution.
  • Figure 2 compares the stabilizing effect of histidine to acetate and citrate on IL-2 aggregation induced by heating the protein solution at 1 C°/min from 25 °C to 95 °C.
  • the present invention is a pharmaceutical composition or formulation of IL-2 or variants (muteins) thereof stabilized with histidine.
  • the composition comprises a mixture resulting in a solution of low ionic strength (e.g. ⁇ 0.1) and includes other stabilizers such as sugars and amino acids, preferably sucrose and glycine.
  • the formulation may include from 0 to 0.9 wt. % NaCl.
  • the composition is albumin-free and the formulation in lyophilized form can be rapidly reconstituted ( ⁇ 1 minute) with water.
  • the composition solubilizes under physiologically acceptable pH conditions, preferably at a pH ranging from about 5.0 to about 6.5, without the use of surfactants such as sodium dodecyl sulfate.
  • the reconstituted solution is near isotonicity and can be administered both subcutaneously and intravenously.
  • the IL-2 of the composition is a mutein having a single amino acid substitution, preferably the N88R variant described in WO 99/60128.
  • the very preferred composition has a protein concentration of 1-5 mg/ml and comprises the following in aqueous form (on a wt/wt basis):
  • LL-2 includes both active wild type IL-2 and its biologically active variants or muteins such as those described in WO 99/60128.
  • IL-2(N88R) which is a recombinant mutein of human IL-2, with asparagine (N) at amino acid position 88 mutated to arginine (R).
  • This mutein was expressed from Chinese hamster ovary (CHO) cells and comprised a mixture of both glycosylated and non-glycosylated forms. It is described in WO 99/60128 cited above as a related application.
  • the objective that led to this invention was the need to identify a lyophilized dosage form for the preferred IL-2 mutein that was albumin-free with acceptable stability.
  • the bioassay for IL-2 was an insensitive measure of stability
  • stable or stable mean reduction of soluble IL-2 quantity by reverse- phase HPLC to no less than 90% of original soluble quantity after storage for four months at 40 °C(see tables 3 and 4 below).
  • Additional stability-indicating assays employed included Aggregation Index, a measure of aggregation by UV/VIS spectrophotometry and determination of soluble aggregates by size-exclusion HPLC. In addition to a stable product, rapid reconstitution (less than 1 minute) of the lyophilisate is highly preferred.
  • the formulation in a lyophilized dosage form with acceptable stability which could be easily lyophilized in production freeze dryers was desired.
  • IL-2(N88R) readily aggregates in the liquid state and the aggregation was pH-dependent.
  • Two preformulation stability studies were conducted: a pH profile of IL- 2(N88R) and stability in the presence of different buffer excipients. The objectives of these studies were to identify a suitable pH range for IL-2(N88R) and a suitable buffering excipient for aqueous stability (reduced aggregation potential).
  • IL-2 solutions were prepared with different pH conditions and stored under accelerated temperature conditions (40 °C). Samples were analyzed at different time intervals and rates of aggregation calculated.
  • the optimal pH range for low aggregation rates was identified between pH 5.0 and 6.5. Histidine, acetate, and citrate were identified as pharmaceutical buffering agents for IL-2(N88R) in this pH range and were evaluated at a concentration of 20 mM in IL-2 (N88R) solutions containing 1 mg/ml IL-2 (N88R) and 150 mM (0.9 wt%) NaCl. These samples were heated from 25 °C to 95 °C at 1 °C per minute and precipitation was monitored by UV spectrophotometry at 350 m.
  • histidine significantly stabilized IL-2(N88R) over the other buffer excipients at pH 5.5 as indicated by an increase in the onset temperature of precipitation.
  • the onset temperatures in the presence of citrate, acetate, and histidine were 62 °C, 64 °C, and 70 °C, respectively.
  • Table 1 shows the onset precipitation temperatures of LL-2(N88R) in the presence of these three buffering agents.
  • the onset precipitation temperature was arbitrarily defined as the temperature at which the optical density at 350 nm (OD 350 ) reaches a certain level (0.2 and 1.0 in the case of OD 350 ).
  • the precipitation temperature of IL-2(N88R) in the presence of histidine was several degrees higher than those in the presence of the other two buffering agents. This example demonstrated that histidine may be a specific stabilizer in addition to being used as a buffering agent for IL-2(N88R) in the liquid state.
  • lyophilized IL- 2(N88R) was prepared from different aqueous formulations (see Table 2). Most of the formulations contained 2 wt% glycine as a bulking agent and 1 wt% sucrose as a stabilizer. Mannitol at 5 wt% was used in a formulation as a comparator to Proleukin ® , a commercialized product of IL-2. Two surfactants, Tween 80 and Pluronic F68 both at 0.1 wt%, were evaluated for prevention of protein surface adsorption and aggregation. All the formulations contained either histidine or citrate as a buffering agent with a pH adjusted to 5.5.
  • Citrate was included to distinguish the stabilizing effect of histidine from that of citrate at pH 5.5. These lyophilized formulations were stored at 40°C and were analyzed by a number of analytical methods that included UVVIS spectrophotometry, SEC-HPLC, and RP-HPLC.
  • Table 3 shows the stability of IL-2(N88R) in a number of formulations as assessed by UV/VIS spectrophotometry for aggregation, amount of soluble aggregates by size-exclusion HPLC (SEC-HPLC), and percent recovery of the protein by reverse-phase HPLC (RP-HPLC). Samples were analyzed after lyophihzation and stored at an accelerated storage temperature of 40°C for four months. The lyophihzation process did not change the net aggregation index of IL-2(N88R) from the pre-lyophilization state, suggesting that IL-2(N88R) tolerated the lyophihzation process with respect to protein aggregation precipitation.
  • the total recovery of soluble IL-2(N88R) after lyophihzation and storage was determined by RP-HPLC (Table 3).
  • the recovery of IL-2(N88R) after lyophihzation was greater than about 96% for all formulations except for the formulation containing mannitol. After storage of these formulations at 40°C for 4 months, approximately 92% of IL-2(N88R) was recovered in formulations A and F containing 2% glycine, 1% sucrose and 20 mM (0.31 wt%) histidine containing 1 and 5 mg/ml IL-2(N88R).
  • Wild-type IL-2 was also lyophilized from an aqueous formulation of the same composition as formulation A.
  • the stability data for the wild-type IL-2 at 40 °C was comparable to those for IL-2(N88R) (Table 4).
  • Human LL-2 has 133 amino acids that form six helical structures (A-F). Four of these helixes form what is termed a tetra-helix bundle motif.
  • the intramolecular disulfide bond between cys 58 and cys 105 is located on the extended loops between the helices.
  • the free cys 125 is located on helix F that incorporates amino acids 117-133.
  • histidine is a specific stabilizer of IL-2 suggests that histidine may interact with IL-2 in a specific manner which results in stabilizing the molecule in both the aqueous and lyophilized states.
  • One of the major mechanisms of instability of IL-2 is aggregation that results from the formation of oligomers due to thiol- disulfide exchange reactions. Hence, one can hypothesize that histidine may in fact inhibit or reduce the thiol-disulfide exchange reactions in IL-2.
  • the electron distribution around a sulfur atom in a thiol can be influenced by the presence of nearby charges and through-bond inductive effects which can alter the pK, of the thiol.
  • increased reactivity of the thiols in the thiol/disulfide exchange can be attributed to the lowering of its pK, due to the presence of either nearby positive charges or peptide dipole contributions from a nearby alpha-helical structure.
  • His-Glu ionic interactions may also create steric hindrance that would further reduce the rate-determining step in the thiol/disulfide exchange which is the formation of an intermediate transition state between the three participating sulfur atoms.
  • the accessibility of histidine to the glutamic acid residues is very likely because the disulfide bond is located on an extended loop on the protein surface.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Train Traffic Observation, Control, And Security (AREA)
  • Control Of Motors That Do Not Use Commutators (AREA)
  • Sub-Exchange Stations And Push- Button Telephones (AREA)

Abstract

L'invention concerne une préparation pharmaceutique stable comprenant une interleukine 2 humaine ou un variant de celle-ci et une dose stabilisatrice d'histidine. Une formulation préférée comprend notamment de la glycine et de la saccharose ainsi qu'un variant d'IL-2 présentant une mutation simple, N88R. La formulation préférée se présente sous forme lyophilisée qui, après reconstitution à l'aide d'un diluant aqueux, produit une solution dont le pH se situe entre environ 5,0 et 6,5.
EP01952296A 2000-06-28 2001-06-27 Interleukine 2 stabilisee Expired - Lifetime EP1370280B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/605,577 US6689353B1 (en) 2000-06-28 2000-06-28 Stabilized interleukin 2
US605577 2000-06-28
PCT/US2001/020675 WO2002000243A2 (fr) 2000-06-28 2001-06-27 Interleukine 2 stabilisee

Publications (2)

Publication Number Publication Date
EP1370280A2 true EP1370280A2 (fr) 2003-12-17
EP1370280B1 EP1370280B1 (fr) 2010-06-16

Family

ID=24424265

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01952296A Expired - Lifetime EP1370280B1 (fr) 2000-06-28 2001-06-27 Interleukine 2 stabilisee

Country Status (24)

Country Link
US (1) US6689353B1 (fr)
EP (1) EP1370280B1 (fr)
JP (3) JP5522878B2 (fr)
KR (1) KR100799402B1 (fr)
CN (1) CN1523997B (fr)
AR (1) AR029139A1 (fr)
AU (1) AU2001273063A1 (fr)
BR (1) BR0112101B1 (fr)
CA (1) CA2413334C (fr)
CO (1) CO5290308A1 (fr)
CU (1) CU23536A3 (fr)
DE (1) DE60142412D1 (fr)
DO (1) DOP2001000197A (fr)
EC (1) ECSP014106A (fr)
ES (1) ES2344729T3 (fr)
HN (1) HN2001000139A (fr)
IL (2) IL153587A0 (fr)
MX (1) MXPA03000046A (fr)
MY (1) MY128629A (fr)
PE (1) PE20020127A1 (fr)
SV (1) SV2002000512A (fr)
TW (1) TWI235063B (fr)
UY (1) UY26805A1 (fr)
WO (1) WO2002000243A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10035836B1 (en) 2014-08-11 2018-07-31 Delinia, Inc. Modified IL-2 variants that selectively activate regulatory T cells
US10174091B1 (en) 2017-12-06 2019-01-08 Pandion Therapeutics, Inc. IL-2 muteins
US10294287B2 (en) 2016-01-20 2019-05-21 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10676516B2 (en) 2017-05-24 2020-06-09 Pandion Therapeutics, Inc. Targeted immunotolerance
US10946068B2 (en) 2017-12-06 2021-03-16 Pandion Operations, Inc. IL-2 muteins and uses thereof
US10961310B2 (en) 2017-03-15 2021-03-30 Pandion Operations, Inc. Targeted immunotolerance
US11077172B2 (en) 2016-11-08 2021-08-03 Delinia, Inc. IL-2 variants for the treatment of psoriasis
US11739146B2 (en) 2019-05-20 2023-08-29 Pandion Operations, Inc. MAdCAM targeted immunotolerance
US11981715B2 (en) 2020-02-21 2024-05-14 Pandion Operations, Inc. Tissue targeted immunotolerance with a CD39 effector
USRE50550E1 (en) 2017-12-06 2025-08-26 Pandion Operations, Inc. IL-2 muteins and uses thereof

Families Citing this family (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8531276B2 (en) * 2000-03-15 2013-09-10 Logitech Europe S.A. State-based remote control system
US6689353B1 (en) * 2000-06-28 2004-02-10 Bayer Pharmaceuticals Corporation Stabilized interleukin 2
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
WO2004028557A1 (fr) * 2002-09-26 2004-04-08 Shionogi & Co., Ltd. Compositions de proteines stabilisees
WO2005113147A2 (fr) 2004-04-08 2005-12-01 Biomatrica, Inc. Integration du stockage et de la gestion d'echantillons pour les sciences de la vie
US20060099567A1 (en) * 2004-04-08 2006-05-11 Biomatrica, Inc. Integration of sample storage and sample management for life science
CN101171033A (zh) 2005-03-04 2008-04-30 戴纳瓦克斯技术公司 包含具免疫刺激序列iss之寡核苷酸的疫苗：其中iss与抗原缀合并通过缓冲条件和其他赋形剂稳定
EP2001500A4 (fr) * 2006-03-10 2010-07-28 Dyax Corp Formulations d'écallantide
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
EP1852108A1 (fr) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG Compositions d'inhibiteurs de la DPP IV
EP2540725A1 (fr) 2006-05-04 2013-01-02 Boehringer Ingelheim International GmbH Polymorphes de 1-((4-Methyl-chinazolin-2-yl)methyl)-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-amino-piperidin-1-yl)xanthin
US7879805B2 (en) 2007-06-01 2011-02-01 Acologix, Inc. High temperature stable peptide formulation
PE20091730A1 (es) 2008-04-03 2009-12-10 Boehringer Ingelheim Int Formulaciones que comprenden un inhibidor de dpp4
DE102008023820A1 (de) 2008-05-08 2009-11-12 Aicuris Gmbh & Co. Kg Mittel zur Behandlung und/oder Prophylaxe einer Autoimmunerkrankung und zur Bildung von Regulatorischen T-Zellen
BRPI0916997A2 (pt) 2008-08-06 2020-12-15 Boehringer Ingelheim International Gmbh Inibidor de dpp-4 e seu uso
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
RS59913B1 (sr) 2008-10-17 2020-03-31 Sanofi Aventis Deutschland Kombinacija insulina i glp-1-agonista
EP2430195B1 (fr) * 2009-05-11 2019-01-23 Biomatrica, INC. Compositions et procédés utilisables à des fins de stockage d'échantillons biologiques
CN102596175A (zh) 2009-07-06 2012-07-18 赛诺菲-安万特德国有限公司 含有甲硫氨酸的水性胰岛素制备物
MY180661A (en) 2009-11-13 2020-12-04 Sanofi Aventis Deutschland Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine
PT3345593T (pt) 2009-11-13 2023-11-27 Sanofi Aventis Deutschland Composição farmacêutica compreendendo despro36exendina- 4(1-39)-lys6-nh2 e metionina
KR20240090632A (ko) 2009-11-27 2024-06-21 베링거 인겔하임 인터내셔날 게엠베하 리나글립틴과 같은 ｄｐｐ－ｉｖ 억제제를 사용한 유전자형 검사된 당뇨병 환자의 치료
CN102946875A (zh) 2010-05-05 2013-02-27 贝林格尔.英格海姆国际有限公司 组合疗法
WO2012018639A2 (fr) 2010-07-26 2012-02-09 Biomatrica, Inc. Compositions de stabilisation d'adn, d'arn, de protéines salivaires et d'autres échantillons biologiques lors du transport et du stockage à températures ambiantes
EP2598660B1 (fr) 2010-07-26 2017-03-15 Biomatrica, INC. Compositions de stabilisation d'adn, d'arn, de protéines dans le sang et d'autres échantillons biologiques lors du transport et du stockage à températures ambiantes
PL2611458T3 (pl) 2010-08-30 2017-02-28 Sanofi-Aventis Deutschland Gmbh Zastosowanie AVE0010 do produkcji leku do leczenia cukrzycy typu 2
WO2012065086A1 (fr) 2010-11-12 2012-05-18 Nektar Therapeutics Conjugués d'une fraction il-2 et d'un polymère
AR083878A1 (es) 2010-11-15 2013-03-27 Boehringer Ingelheim Int Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento
EP2646051A4 (fr) * 2010-12-02 2014-05-28 Oncolytics Biotech Inc Formulations de virus liquides
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
AR087693A1 (es) 2011-08-29 2014-04-09 Sanofi Aventis Deutschland Combinacion farmaceutica para uso en el control glucemico en pacientes con diabetes de tipo 2
TWI559929B (en) 2011-09-01 2016-12-01 Sanofi Aventis Deutschland Pharmaceutical composition for use in the treatment of a neurodegenerative disease
JP6218811B2 (ja) 2012-05-14 2017-10-25 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｓｉｒｓ及び／又は敗血症の治療に用いるｄｐｐ−４阻害薬としてのキサンチン誘導体
JP6224084B2 (ja) 2012-05-14 2017-11-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 糸球体上皮細胞関連障害及び／又はネフローゼ症候群の治療に用いるｄｐｐ−４阻害薬としてのキサンチン誘導体
US9725703B2 (en) 2012-12-20 2017-08-08 Biomatrica, Inc. Formulations and methods for stabilizing PCR reagents
CN103063829B (zh) * 2012-12-21 2015-01-14 杭州茂天赛科技有限公司 一种冻存液
GB201403775D0 (en) 2014-03-04 2014-04-16 Kymab Ltd Antibodies, uses & methods
ES2786373T3 (es) 2014-06-10 2020-10-09 Biomatrica Inc Estabilización de trombocitos a temperaturas ambiente
EP3229828B1 (fr) 2014-12-12 2023-04-05 Sanofi-Aventis Deutschland GmbH Formulation à rapport fixe d'insuline glargine/lixisenatide
TWI748945B (zh) 2015-03-13 2021-12-11 德商賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患治療
TW201705975A (zh) 2015-03-18 2017-02-16 賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患之治療
WO2017062832A1 (fr) 2015-10-08 2017-04-13 Nektar Therapeutics Combinaison d'un agoniste sélectif de l'il-2rbeta et d'un agoniste de l'il-15 à action prolongée
KR20250047404A (ko) 2015-12-08 2025-04-03 바이오매트리카 인코포레이티드 적혈구 침강 속도의 감소
CN109310697A (zh) 2016-06-10 2019-02-05 勃林格殷格翰国际有限公司 利格列汀和二甲双胍的组合
US9567399B1 (en) 2016-06-20 2017-02-14 Kymab Limited Antibodies and immunocytokines
RU2769282C2 (ru) 2016-06-20 2022-03-30 Кимаб Лимитед Анти-PD-L1 и IL-2 цитокины
EP3534947A1 (fr) 2016-11-03 2019-09-11 Kymab Limited Anticorps, combinaisons comprenant des anticorps, biomarqueurs, utilisations et procédés
KR102777151B1 (ko) 2017-11-21 2025-03-05 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티 인터루킨-2의 부분 효능제
CN111918665B (zh) 2018-03-28 2024-11-26 阿森迪斯药物肿瘤股份有限公司 Il-2缀合物
IL293471A (en) 2019-12-17 2022-08-01 Amgen Inc Dual interleukin-2 / tnf receptor agonist for use in medicine
WO2021127487A2 (fr) 2019-12-20 2021-06-24 Regeneron Pharmaceuticals, Inc. Nouveaux agonistes d'il2 et leurs procédés d'utilisation
US11633488B2 (en) 2020-01-10 2023-04-25 Bright Peak Therapeutics Ag Modified IL-2 polypeptides and uses thereof
WO2021146436A2 (fr) 2020-01-14 2021-07-22 Synthekine, Inc. Méthodes et compositions de mutéines d'il2 biaisées
KR20230019889A (ko) 2020-06-03 2023-02-09 아센디스 파마 온콜로지 디비전 에이/에스 Il-2 서열 및 이의 용도
TW202406932A (zh) 2020-10-22 2024-02-16 美商基利科學股份有限公司 介白素2-Fc融合蛋白及使用方法
US20230398183A1 (en) * 2020-11-13 2023-12-14 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Pharmaceutical composition comprising human interleukin 2 variant or derivative thereof and use thereof
TW202317623A (zh) 2021-06-14 2023-05-01 美商再生元醫藥公司 基於il2之治療劑及其使用方法

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60215631A (ja) * 1984-04-09 1985-10-29 Takeda Chem Ind Ltd インタ−ロイキン−２組成物
EP0158487B1 (fr) * 1984-04-09 1991-08-28 Takeda Chemical Industries, Ltd. Composition stable d'interleukine-2
JPH0645551B2 (ja) * 1986-01-07 1994-06-15 塩野義製薬株式会社 インタ−ロイキン−２組成物
JPH0229016A (ja) * 1989-06-09 1990-01-31 Alpine Electron Inc イコライザ装置
US5358708A (en) 1993-01-29 1994-10-25 Schering Corporation Stabilization of protein formulations
US5656730A (en) * 1995-04-07 1997-08-12 Enzon, Inc. Stabilized monomeric protein compositions
US6267958B1 (en) * 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
US5763401A (en) 1996-07-12 1998-06-09 Bayer Corporation Stabilized albumin-free recombinant factor VIII preparation having a low sugar content
AU8985898A (en) * 1997-07-31 1999-02-22 Rhodia Chimie Cosmetic composition comprising a functionalised polyorganosiloxane
DZ2788A1 (fr) * 1998-05-15 2003-12-01 Bayer Ag Agonistes et antagonistes selectifs à IL-2.
US6689353B1 (en) * 2000-06-28 2004-02-10 Bayer Pharmaceuticals Corporation Stabilized interleukin 2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0200243A2 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10035836B1 (en) 2014-08-11 2018-07-31 Delinia, Inc. Modified IL-2 variants that selectively activate regulatory T cells
US10774126B2 (en) 2016-01-20 2020-09-15 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US11535657B2 (en) 2016-01-20 2022-12-27 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10294287B2 (en) 2016-01-20 2019-05-21 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10875901B2 (en) 2016-01-20 2020-12-29 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10766938B2 (en) 2016-01-20 2020-09-08 Delinia, Inc. Nucleic acid encoding human IL-2 variant
US11077172B2 (en) 2016-11-08 2021-08-03 Delinia, Inc. IL-2 variants for the treatment of psoriasis
US10961310B2 (en) 2017-03-15 2021-03-30 Pandion Operations, Inc. Targeted immunotolerance
US10676516B2 (en) 2017-05-24 2020-06-09 Pandion Therapeutics, Inc. Targeted immunotolerance
US11466068B2 (en) 2017-05-24 2022-10-11 Pandion Operations, Inc. Targeted immunotolerance
US10174092B1 (en) 2017-12-06 2019-01-08 Pandion Therapeutics, Inc. IL-2 muteins
US11091526B2 (en) 2017-12-06 2021-08-17 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11091527B2 (en) 2017-12-06 2021-08-17 Pandion Operations, Inc. IL-2 muteins and uses thereof
US10946068B2 (en) 2017-12-06 2021-03-16 Pandion Operations, Inc. IL-2 muteins and uses thereof
US10174091B1 (en) 2017-12-06 2019-01-08 Pandion Therapeutics, Inc. IL-2 muteins
US11779632B2 (en) 2017-12-06 2023-10-10 Pandion Operation, Inc. IL-2 muteins and uses thereof
US11945852B2 (en) 2017-12-06 2024-04-02 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11965008B2 (en) 2017-12-06 2024-04-23 Pandion Operations, Inc. IL-2 muteins and uses thereof
USRE50550E1 (en) 2017-12-06 2025-08-26 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11739146B2 (en) 2019-05-20 2023-08-29 Pandion Operations, Inc. MAdCAM targeted immunotolerance
US11981715B2 (en) 2020-02-21 2024-05-14 Pandion Operations, Inc. Tissue targeted immunotolerance with a CD39 effector

Also Published As

Publication number Publication date
CN1523997A (zh) 2004-08-25
AR029139A1 (es) 2003-06-04
ECSP014106A (es) 2002-02-25
IL153587A (en) 2007-12-03
EP1370280B1 (fr) 2010-06-16
BR0112101B1 (pt) 2017-11-14
WO2002000243A2 (fr) 2002-01-03
UY26805A1 (es) 2002-01-31
CU23536A3 (es) 2010-06-17
SV2002000512A (es) 2002-07-03
JP2012211166A (ja) 2012-11-01
IL153587A0 (en) 2003-07-06
CA2413334A1 (fr) 2002-01-03
US6689353B1 (en) 2004-02-10
JP2004532791A (ja) 2004-10-28
CN1523997B (zh) 2010-09-01
KR20030016312A (ko) 2003-02-26
MY128629A (en) 2007-02-28
WO2002000243A3 (fr) 2003-10-02
CA2413334C (fr) 2011-03-08
PE20020127A1 (es) 2002-04-27
JP5522878B2 (ja) 2014-06-18
DE60142412D1 (de) 2010-07-29
JP5989728B2 (ja) 2016-09-07
CO5290308A1 (es) 2003-06-27
KR100799402B1 (ko) 2008-01-30
DOP2001000197A (es) 2003-01-15
AU2001273063A1 (en) 2002-01-08
TWI235063B (en) 2005-07-01
MXPA03000046A (es) 2003-06-19
HN2001000139A (es) 2003-12-11
ES2344729T3 (es) 2010-09-06
JP2015007114A (ja) 2015-01-15
BR0112101A (pt) 2004-07-06

Similar Documents

Publication Publication Date Title
CA2413334C (fr) Interleukine 2 stabilisee
KR100656125B1 (ko) 장기 안정화 제제
US5919443A (en) Stable lyophilized pharmaceutical preparations of G-CSF
KR100457485B1 (ko) 안정한 트란스글루타미나제 제형 및 이의 제조 방법
US20060079459A1 (en) Stabilized compositions comprising tissue factor pathway inhibitor protein or tissue factor pathway inhibitor variant proteins
US20030104996A1 (en) L-methionine as a stabilizer for NESP/EPO in HSA-free formulations
JP2005068158A (ja) 安定化された液体のポリペプチド含有薬学的組成物
EP1260230A1 (fr) Preparations stabilisees a long terme
EP1706150B1 (fr) Formulation liquide stable d'hormones de croissance
EP1641486B1 (fr) Solutions aqueuses stables d'erythropoietine humaine ne contenant pas d'albumine serique
EP2142174B1 (fr) Formulations aqueuses stables de g-csf
JP2004538275A (ja) ヒトインターフェロン−β配合物
WO2008066322A1 (fr) Composition pharmaceutique stable exempte de hsa et d'antioxydant et comprenant de l'interféron bêta
JPH06247870A (ja) インターロイキン−６を含有する医薬製剤
HK1135329B (en) Stable aqueous g-csf formulations

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17P Request for examination filed

Effective date: 20040402

RBV Designated contracting states (corrected)

Designated state(s): DE ES FR GB IT

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: AICURIS GMBH & CO. KG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: AICURIS GMBH & CO. KG

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): DE ES FR GB IT

REF Corresponds to:

Ref document number: 60142412

Country of ref document: DE

Date of ref document: 20100729

Kind code of ref document: P

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2344729

Country of ref document: ES

Kind code of ref document: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20110317

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60142412

Country of ref document: DE

Effective date: 20110316

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60142412

Country of ref document: DE

Representative=s name: BOEHMERT & BOEHMERT, DE

Ref country code: DE

Ref legal event code: R082

Ref document number: 60142412

Country of ref document: DE

Representative=s name: BOEHMERT & BOEHMERT ANWALTSPARTNERSCHAFT MBB -, DE

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 17

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20190624

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20190619

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20190619

Year of fee payment: 19

Ref country code: ES

Payment date: 20190719

Year of fee payment: 19

Ref country code: DE

Payment date: 20190628

Year of fee payment: 19

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60142412

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20200627

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200627

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210101

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20211103

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200628

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200627